A high-grade glioma metastasis to the thoracic spine: illustrative case and a brief review

Abstract

Spinal metastasis of high grade glioma (HGG) is a rare but serious clinical occurrence that can significantly impact patient prognosis and quality of life. Although the majority of HGG metastases are confined intracranially, extracranial spread, including spinal metastasis, has been increasingly recognized in recent years. Spinal involvement may occur through hematogenous spread, direct extension, or cerebrospinal fluid dissemination, with the most common sites being the vertebral bodies and epidural space. The clinical presentation of spinal metastasis often includes worsening back pain and neurological deficits which may require urgent surgery. Authors present a mini review of this important clinical condition with an insight of their own case and possibilities of treatment which is often limited due to the aggressive nature of HGG and the challenging management of spinal metastases. Surgical resection and oncologic therapy still remain the commonly established options to be employed, nevertheless outcomes remain poor and median survival times are generally short. Although rare, spinal metastasis of HGG needs more research in order to better understand the pathophysiology, optimal management strategies and long-term outcomes for affected patients.

Introduction

High-grade gliomas (HGGs) are the most common malignant primary brain tumors, with a median survival time of approximately fifteen months following the implementation of the Stupp treatment protocol. HGGs account for up to 50% of all glial tumors of the brain [11]. Traditionally, the identification of diffuse gliomas was based on their histologic (i.e., morphologic) features and gradedaccording to the degree of malignancy, based on the presence or absence of necrosis and the level of cellular proliferation. The latest World Health Organization (WHO) classification of tumors of the central nervous system (CNS) recognizes the importance of molecular profiles and genetic markers in establishing an accurate diagnosis and prognosis [2]. Spinal drop metastases of HGGs are rarely reported, and fewer than 5% of patients present with clinically evident symptoms [4, 10]. However, autopsy studies suggest that this percentage may exceed 25% due to leptomeningeal spread [11]. The most common routes of metastatic dissemination include intraparenchymal extension along white matter tracts, cerebrospinal fluid (CSF) pathways, or hematogenous spread. Leptomeningeal dissemination with clinical symptoms occurs in approximately 2% of cases and is typically considered a late-stage and fatal consequence of HGG [10]. Currently, there are no established treatment guidelines for HGGs with spinal canal involvement. We present the case of a 75-year-old female patient who developed paraparesis sixteen months after surgical excision of a high-grade glioma in the right frontal lobe.

Case report

A 75-year-old female patient previously underwent surgical treatment at our Department, where gross total resection (GTR) of a right-sided high-grade glioma (HGG) in the frontal lobe was performed in August 2023 (Fig. 1). Due to the extent of resection, an intraoperative breach of the ventricular wall was noted. Histological analysis revealed densely cellular tumor tissue composed of clusters of atypical glial cells with hyperchromatic small nuclei and scant cytoplasm. Atypical mitoses, extensive areas of necrosis, and pathologically altered blood vessels with signs of endothelial proliferation were observed. Immunohistochemistry was positive for GFAP, S100, and NSE, while negative for CKAE1/AE3, CK7, CK20, TTF1, Melan-A, synaptophysin, and chromogranin. Further immunohistochemical profiling showed GFAP+, OLIG2+, IDH1−, ATRX retained expression (no mutation), H3G3−, p53+, and a Ki-67 proliferation index of up to 50%. Molecular testing revealed a p.R132H (c.395G > A) mutation in codon 132, exon 4 of the IDH1 gene. These findings confirmed the diagnosis of astrocytoma, IDH-mutant, WHO grade 4. Postoperatively, the patient underwent standard oncological treatment according to the Stupp protocol, including radiotherapy (RT) at a dose of 60 Gy and concomitant chemotherapy (CT) with Temozolomide (TMZ). Follow-up MRI scans were performed at four, seven, and fifteen months postoperatively, all of which showed no signs of tumor recurrence. No neurological deficits were observed during this period. However, sixteen months after the initial surgery, the patient developed new symptoms—specifically, a sudden onset of motor weakness in both legs. She was evaluated by a neurologist, and MRI scans of the brain and entire neuroaxis were performed. While no intracranial recurrence was detected (Fig. 2), an extramedullary-intradural tumor lesion was identified at the T7–T8 spinal level (Fig. 3). The patient was re-admitted to our Department. Upon admission, laboratory findings were unremarkable, the patient was afebrile, had a Glasgow Coma Scale (GCS) score of 15, and required urinary catheterization due to incontinence. No neurological deficits were noted in the upper limbs. However, paraparesis was present, and muscle strength in both legs was graded as 2/5 on the Medical Research Council (MRC) scale. The patient underwent surgery under general anesthesia without complications. A laminectomy of T6 to T8 vertebrae was performed, and the tumor was microsurgically removed with the assistance of neuronavigation to ensure precise resection along tumor borders. Intraoperative evoked potentials were not obtainable. The dura mater was sutured with 4 − 0 sutures and sealed with fibrin glue. Intraoperative frozen section analysis did not yield a definitive diagnosis, but final histopathological evaluation confirmed a high-grade glial tumor, histologically consistent with the previously resected tumor (Fig. 4).

Fig. 1.

: Preoperative T1-enhanced MRI scan revealed a large solid and cystic tumor of the right frontal lobe with compression of the right-sided ventricular system and significant contralateral brain shift. Arrows point the tumor lesion in its axial (A), coronal (B) and sagittal (C) plane

Fig. 2.

: Postoperative follow-up T2 FLAIR MRI scan revealed no tumor recurrence, no brain shift, normal size of ventricular system. Arrow shows the point of intraoperative breach of the ventricular wall

Fig. 3.

: Postoperative follow-up T2 MRI scan revealed an intradural-extramedullar tumor lesion at the site of T7 and T8. Arrows point to the lesion in its sagittal (A) and axial (B) plane

Fig. 4.

: Tumor tissue with an area of ​​intense apoptosis of tumor cells (upper third of the image),

haematoxylin, eosin, ×200 (A), CD56 (neural cell adhesion molecule - NCAM) positivity of tumor cells, haematoxylin, anti-CD56 antibody, ×200 (B), GFAP (glial fibrillary acidic protein) positivity of tumor cells, haematoxylin, anti-GFAP antibody, ×200 (C), S100 positivity of tumor cells, haematoxylin, anti-S100 antibody, ×200 (D), Tumor cells with numerous mitoses and apoptotic bodies, haematoxylin eosin, ×400 (E), GFAP positivity of primary brain tumor, haematoxylin, anti-GFAP antibody, ×200 (F)

The postoperative course was uneventful, with no complications such as wound dehiscence, infection, or CSF leakage. Physical rehabilitation was initiated under the supervision of a physiatrist. Muscle strength in both legs remained unchanged postoperatively (2/5). The patient was discharged eight days after surgery. Twenty days postoperatively, she was seen by an oncologist who recommended further oncological treatment—specifically, radiotherapy and TMZ—conditional on a Karnofsky Performance Status (KPS) score greater than 60. Unfortunately, the patient died two months after the second surgery.

Discussion

Treatment of high-grade gliomas (HGG), including all subtypes, remains challenging despite novel approaches and methods. Treatment outcomes depend on various factors such as patient age, gender, extent of tumor resection, and performance status scores including the Karnofsky and Eastern Cooperative Oncology Group (ECOG) scales [7]. In our 2020 study involving a cohort of sixty-three patients, we found no significant difference in overall or progression-free survival compared to other studies [7]. Additionally, no cases of spinal metastases were observed among patients surgically treated over a five-year period. This supports the conclusion that HGG-associated spinal metastases are exceedingly rare. One possible explanation is that most patients succumb to the primary intracranial tumor before spinal metastasis becomes clinically apparent. Nonetheless, spinal metastases from HGG have beenreported in the literature. In our case, the likely mechanism of spinal metastasis is drop metastasis due to intraoperative disruption of the ventricular system during the initial surgery, consistent with known pathways of tumor dissemination. As in our case, surgical intervention remains the primary treatment option in patients with sudden neurological deterioration. However, due to the infiltrative and diffuse nature of HGG, treatment outcomes are variable. Recent data suggest an increasing incidence of spinal metastases from HGG, indicating that clinicians should maintain a high index of suspicion in patients with prior intracranial HGG who present with new symptoms not attributable to the original tumor site [5]. Our patient’s metastasis at the T8 level aligns with reports that HGGs often metastasize to the lower thoracic, lumbar, or lumbosacral spinal segments [12]. Although we identified an extramedullary, intradural metastatic lesion, the literature more commonly describes metastases to the cauda equina nerve roots or the base of the thecal sac [12]. Symptoms typically reflect the anatomical location, including radicular pain in the limbs, paraparesis, and interscapular or lumbar pain. Leptomeningeal metastases occur in approximately 14% of cases, while intramedullary metastases are reported in just over 1% [12]. According to the 2021 WHO classification of CNS tumors, IDH mutations now define low-grade diffuse astrocytomas. These tumors generally have a better prognosis than those defined under the 2016 WHO classification. Recent studies group IDH-mutant grade 2 and grade 3 astrocytomas as “diffuse low-grade astrocytomas” due to their similar prognoses. Furthermore, IDH-mutant grade 3 astrocytomas differ significantly from IDH-wildtype grade 4 astrocytomas (i.e., glioblastomas) in molecular profile and clinical behavior, and the traditional grouping of all “high-grade astrocytomas” (grades 3 and 4) is now considered inappropriate [13]. This evolving classification system creates diagnostic overlap in high-grade gliomas. Kleinschmidt-DeMasters reviewed leptomeningeal (LM) and dural spread in adult high-grade astrocytomas, including glioblastomas (GB), IDH-mutant WHO grade 4 astrocytomas, and high-grade astrocytomas with piloid features (HGAP), covering cases from 2018 to 2022. The study confirmed that both IDH-wildtype and IDH-mutant tumors can present with LM or dural spread, even years after initial diagnosis. Importantly, HGAP, although rare, was also found to metastasize, reinforcing the need for vigilance in clinical practice [6]. In that series, four patients had astrocytoma, IDH-mutant, WHO grade 4 at the time of metastatic diagnosis [6]. By comparison, our case may be among the rare documented instances of spinal metastasis from a WHO 2021-defined high-grade IDH-mutant astrocytoma. Despite updates in classification, the distinction between high-grade gliomas remains nuanced. In 2023, Amelot et al. published a large retrospective study spanning 12 years across French hospitals, identifying 14 patients with spinal cord metastases from GB. The median spinal metastasis-free survival was 13.6 months, and 57% of patients were non-ambulatory at diagnosis. Median overall survival was 3.3 months, reflecting the aggressive nature of the disease [1]. Similarly, Lawton et al. conducted a 32-year retrospective study including 42 cases. The overall survival in patients with spinal cord GB metastases was comparable between the studies—3.3 versus 3.7 months. The mean patient age in Lawton’s study was 43 years [8]. Diagnosis of spinal metastasis typically relies on MRI, especially in patients with known intracranial GB. Amelot et al. recommended confirmatory biopsy or surgical resection for histological diagnosis [1]. According to Nakata et al., external beam radiotherapy remains the gold standard for palliative management, particularly for pain relief and motor function preservation. Total or partial surgical resection is rarely performed, as it has minimal impact on survival or functional recovery [9]. These findings reinforce that spinal metastases from GB carry a dismal prognosis, with very short overall survival. In a serial autopsy study, about 25% of patients with intracranial GB exhibited spinal subarachnoid seeding, though the actual incidence remains unknown [3]. The increasing number of reported spinal GB metastases may be attributed to improved survival and evolving tumor behavior following surgical and oncological treatments [12].

In conclusion, despite all modern treatment options, the overall survival of patients with high-grade gliomas remains poor. Management of spinal metastases is not standardized and largely depends on individualized clinical judgment. Surgical intervention may offer temporary symptom relief, especially in cases of acute neurologic decline, but does not significantly alter disease progression. Future research should aim to clarify treatment algorithms and incorporate molecular profiling to better guide therapeutic decisions and improve patient outcomes.

Author contributions

The authors declare no interests.

Funding

None.

Declarations:

Ethical Approval and Accordance: Ethical approval for this case report was obtained in accordance with the policies of the Ethics Committee of the University Hospital Center Osijek, Croatia. All procedures were conducted in accordance with institutional guidelines and the Declaration of Helsinki. Consent to Participate: Written informed consent to participate in this case report was obtained from the patient’s caregivers. Consent to Publish: Written informed consent for publication of the clinical details and any accompanying images was obtained from the patient’s caregivers. Data Availability Statement: The clinical data supporting the findings are not publicly available due to patient confidentiality but are available from the corresponding author upon reasonable request.

Data availability

The clinical data supporting the findings are not publicly available due to patient confidentiality but are available from the corresponding author upon reasonable request.

Declarations

Competing interests

The authors declare no competing interests.